Benzimidazoles as CNS active agents

Abstract

The present invention relates to compounds of general formula wherein R 1 hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; R 2 is hydrogen or halogen; X 1 is N or CH; X 2 is N or CH; with the proviso that only one of X 1 or X 2 is N; X 3 is C(R) or N; and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and cocaine.

The invention claimed is: 
     
       1. A Compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; 
 R 2  is hydrogen or halogen; 
 X 1  is N or CH; 
 X 2  is N or CH;
 with the proviso that only one of X 1  or X 2  is N; 
 
 X 3  is C(R) or N;
 and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl; 
 
 
       or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof. 
     
     
       2. A compound of formula IA according to  claim 1 , 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; 
 R 2  is hydrogen or halogen; 
 X 3  is C(R) or N;
 and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl; 
 
 
       or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof. 
     
     
       3. The compound of formula IA according to  claim 2 , wherein the compound is
 1-p-Tolyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-Phenyl-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-phenyl-1H-benzoimidazole 
 1-Phenyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 6-(2-Phenyl-2H-pyrazol-3-yl)-1-p-tolyl-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-p-tolyl-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-fluoro-phenyl)-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole 
 1-(2,4-Difluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(2,4-difluoro-phenyl)-1H-benzoimidazole 
 1-(2,4-Difluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole 
 1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole or 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole. 
 
     
     
       4. A compound of formula IA-1 according to  claim 1   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; 
 R 2  is hydrogen or halogen; 
 R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl, 
 
       or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof. 
     
     
       5. A compound of formula IA-1 according to  claim 4  wherein the compound is
 1-p-Tolyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-Phenyl-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-phenyl-1H-benzoimidazole 
 1-Phenyl-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 6-(2-Phenyl-2H-pyrazol-3-yl)-1-p-tolyl-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-p-tolyl-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-(2-phenyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-(2-p-tolyl-2H-pyrazol-3-yl)-1H-benzoimidazole 
 1-(4-Fluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-fluoro-phenyl)-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole 
 1-(2,4-Difluoro-phenyl)-6-[2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(2,4-difluoro-phenyl)-1H-benzoimidazole 
 1-(2,4-Difluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-trifluoromethyl-phenyl)-1H-benzoimidazole 
 1-(4-Chloro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 1-(4-Chloro-2-fluoro-phenyl)-6-[2-(4-chloro-phenyl)-2H-pyrazol-3-yl]-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methoxy-phenyl)-1H-benzoimidazole 
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole or 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-(4-methanesulfonyl-phenyl)-1H-benzoimidazole. 
 
     
     
       6. A compound of formula IA-2 according to  claim 1   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; 
 R 2  is hydrogen or halogen; 
 
       or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof. 
     
     
       7. A compound of formula IA-2 according to  claim 6 , wherein the compounds are
 6-[2-(4-Fluoro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole or 
 6-[2-(4-Chloro-phenyl)-2H-pyrazol-3-yl]-1-pyridin-4-yl-1H-benzoimidazole. 
 
     
     
       8. A compound of formula IB according to  claim 1   
       
         
           
           
               
               
           
         
       
       wherein
 R 1  hydrogen, lower alkyl, halogen or lower alkyl substituted by halogen; 
 R 2  is hydrogen or halogen; 
 X 3  is C(R) or N;
 and R is hydrogen, lower alkyl, halogen, lower alkyl substituted by halogen, lower alkoxy or SO 2 -lower alkyl, 
 
 
       or a pharmaceutically acceptable acid addition salt, a racemic mixture or its corresponding enantiomer and/or optical isomers thereof. 
     
     
       9. A compound according to  claim 1 , wherein the compound is
 1-(4-Fluoro-phenyl)-6-(3-phenyl-3H-imidazol-4-yl)-1H-benzoimidazole 
 6-[3-(4-Chloro-phenyl)-3H-imidazol-4-yl]-1-(4-fluoro-phenyl)-1H-benzoimidazole or 
 1-(4-Fluoro-phenyl)-6-[3-(4-fluoro-phenyl)-3H-imidazol-4-yl]-1H-benzoimidazole. 
 
     
     
       10. A process for the manufacture of a compound of formula I as defined in  claim 1 , which process comprises 
       reacting a compound of formula (1) 
       
         
           
           
               
               
           
         
       
       with a compound of formula (2) 
       
         
           
           
               
               
           
         
       
       to afford a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       and optionally converting the compound obtained into a pharmaceutically acceptable acid addition salt. 
     
     
       11. A compound according to  claim 1  when manufactured by a process according to  claim 10 . 
     
     
       12. A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutical acceptable carrier and/or adjuvant. 
     
     
       13. A method for the treatment of major depression, anxiety disorders, Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, stroke, which method comprises administering a therapeutically effective amount of a compound as defined in  claim 1  to a patient in need thereof.